A Phase III Randomized Trial of the Reduction of Chemotherapy in Philadelphia Chromosome-positive ALL of Young Adults (GRAAPH2014)

A Phase III Study, Randomized, to Evaluate the Reduction of Chemotherapy Intensity in Association With Nilotinib (Tasigna®) in Philadelphia Chromosome-positive (Ph+) ALL of Young Adults (18-59 Years Old) (GRAAPH-2014)

The Primary objective is to assess the non-inferiority of the experimental arm (arm B) compared to the control arm (arm A) in terms of Major Molecular Response (MMolR) after the 4th cycle (MRD4) in patients aged 18-59 years old with de novo Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL)

Study Overview

• Status: Recruiting
• Conditions: Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Nilotinib; Drug: Methotrexate; Drug: Aracytine (Ara C); Drug: Granulocyte Colony-Stimulating Factor (G-CSF); Drug: Depomedrol; Drug: Dexamethasone; Drug: Vincristine; Drug: Imatinib; Drug: 6 Mercaptopurine (6MP)

• Study Type: Interventional
• Enrollment (Anticipated): 265
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hervé Dombret, MDPhD; Phone Number: +33 (0)1 57 27 68 47; Email: herve.dombret@aphp.fr
• Study Contact Backup: Name: Véronique Lhéritier; Phone Number: +33(0)4 78 86 22 39; Email: veronique.lheritier@chu-lyon.fr

Study Locations

• France
  • Paris, France, 75010
    • Recruiting
    • Hôpital Saint Louis
    • Contact: Hervé Dombret, MDPhD; Phone Number: +33 (0)1 57 27 68 47; Email: herve.dombret@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patient

1. Whose blood and bone marrow explorations have been completed before the steroids prephase
2. Aged 18-59 years old with newly-diagnosed non previously treated Ph+ ALL according to WHO 2008 criteria (confirmed diagnosis of the Philadelphia chromosome defined by the reciprocal translocation of chromosomes 9 and 22, t(9;22) and/or presence of the BCR-ABL molecular maker)
3. With ≥ 20% bone marrow blasts
4. With Eastern Cooperative Oncology Group (ECOG) Performans Status ≤ 3
5. With or without central nervous system (CNS) or testis involvement
6. Without evolving cancer (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix) or its chemo- or radio-therapy should be finished at least since 6 months.
7. Having received no previous treatment for this hematological disease (including IT injection)
8. Having signed written informed consent
9. With efficient contraception for women of childbearing age (excluding estrogens and IUD)
10. With health insurance coverage
11. Who have received (or being receiving) the recommended steroid prephase.

Note 1: Secondary ALL (antecedent of chemo- or radio-therapy) can be included Note 2: In case of high vascular risk (see section "study management") the patient will not be able to receive nilotinib unless an ultra sound Doppler of the neck and lower limbs has been performed during the pre-phase and treatment validated by the medical coordinators of the protocol via the secretariat.

Exclusion Criteria:

Patient:

1. Previously treated with Tyrosine Kinase Inhibitor (TKI)
2. With another active malignancy

3. With general or visceral contra-indication to intensive therapy (except if considered related to the ALL):

   1. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.5 x upper limit of normal range (ULN)
   2. Total bilirubin > 1.5 x ULN
   3. Creatinine > 1.5 x ULN or creatinine clearance <50 mL/mn
   4. Serum amylase or lipase > 1.5 x ULN or antecedents of acute pancreatitis

4. With heart failure, including at least one of the following criteria:

   1. Left ventricular ejection fraction (LVEF) <50% or below the lowest normal threshold, as determined by ECG or heart failure (NYHA grade III or IV)
   2. Impossibility to measure the QT interval on ECG
   3. Complete left bundle branch block
   4. Pacemaker
   5. Congenital long QT syndrome of known familial antecedents of long QT syndrome
   6. Antecedents or current ventricular or atrial tachyarrhythmia, clinically significant
   7. Baseline bradycardia (<50 bpm) clinically significant
   8. Corrected QT interval (QTc)> 450 msec established on the mean of 3 baseline ECG
   9. Antecedents of myocardial infarct in the past 6 months
   10. Instable angor within the past 12 months
   11. Any heart condition clinically significant (i.e. congestive heart failure, uncontrolled hypertension)
5. Active uncontrolled infection, any other concurrent disease deemed to interfere with the conduct of the study as judged by the investigator
6. Severe evolving infection, or known HIV or Human T-Lymphotropic Virus type I (HTLV1) seropositivity, or active infection by hepatitis B or C virus
7. Pregnant (beta-HCG) or nursing woman
8. Women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least three months thereafter. Patient not willing to ensure not to beget a child during participation in the study and at least three months thereafter.
9. Having received an investigational treatment or participation in another trial within 30 days prior to entering this study.
10. Not able to bear with the procedures or the frequency of visits planned in the trial.
11. Unable to consent, under tutelage or curators, or judiciary safeguard

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intensive Arm (A); 4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) + Post-SCT Maintenance	Drug: Nilotinib; 400 mg/12h per os D1 to D28 cycles 1-4 300 mg/12h per os D1-D14 interphase; Drug: Methotrexate; 1 g/m2 continuous Intravenous Infusion (CIV) D1 cycles 2 and 4 25 mg/m2 per os D1, D8 interphase; Drug: Aracytine (Ara C); Age<45 years: 3 mg/m2/12h D2, D3 cycles 2 and 4 Age>=45 years: 1.5 mg/m2/12h D2, D3 cycles 2 and 4; Drug: Granulocyte Colony-Stimulating Factor (G-CSF); 5µg/kg/d (SC) D6 until neutrophils > 1 G/L D15 cycles 1 and 3; D6 cycles 2 and 4; Drug: Depomedrol; 40 mg + methotrexate 15 mg + Aracytine (AraC) 40mg IT cycle 1: D1, D8, D15 IT cycles 2 and 4: D9 IT cycle 3: D1; Drug: Dexamethasone; 40 mg per os, D1-D2, D8-D9, D15-D16, D22-D23, cycles 1 and 3; Drug: Vincristine; 2 mg total dose IV, D1 D8 D15 D22 cycles 1 and 3; Drug: Imatinib; 300 mg/12h per os in post-SCT maintenance therapy for during at least 2 years; Drug: 6 Mercaptopurine (6MP); 60 mg/m2 per os, D1 to D14, interphase
Experimental: Light Arm (B); 4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) + Post-SCT Maintenance	Drug: Nilotinib; 400 mg/12h per os D1 to D28 cycles 1-4 300 mg/12h per os D1-D14 interphase; Drug: Methotrexate; 1 g/m2 continuous Intravenous Infusion (CIV) D1 cycles 2 and 4 25 mg/m2 per os D1, D8 interphase; Drug: Granulocyte Colony-Stimulating Factor (G-CSF); 5µg/kg/d (SC) D6 until neutrophils > 1 G/L D15 cycles 1 and 3; D6 cycles 2 and 4; Drug: Depomedrol; 40 mg + methotrexate 15 mg + Aracytine (AraC) 40mg IT cycle 1: D1, D8, D15 IT cycles 2 and 4: D9 IT cycle 3: D1; Drug: Dexamethasone; 40 mg per os, D1-D2, D8-D9, D15-D16, D22-D23, cycles 1 and 3; Drug: Vincristine; 2 mg total dose IV, D1 D8 D15 D22 cycles 1 and 3; Drug: Imatinib; 300 mg/12h per os in post-SCT maintenance therapy for during at least 2 years; Drug: 6 Mercaptopurine (6MP); 60 mg/m2 per os, D1 to D14, interphase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Molecular Response (MMolR)	defined as a breakpoint cluster region (BCR)-Abelson (ABL) ratio < 0.1% in the bone marrow sample of MRD4	4 cycles (4 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity		12 months
Complete remission after cycle 1		day 28
Cumulative incidence of treatment- and transplantation-related mortality		2 years
Cumulative incidence of relapse		10 years
Relapse free survival		10 years
Event-free survival		10 years
overall survival		10 years
T315I mutation	mutations will be assessed by Reverse transcription Quantitative Polymerase Chain Reaction (RQ-PCR) sequencing in case of progression or relapse	10 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: November 19, 2015
• First Submitted That Met QC Criteria: November 19, 2015
• First Posted (Estimate): November 20, 2015

Study Record Updates

• Last Update Posted (Actual): October 21, 2019
• Last Update Submitted That Met QC Criteria: October 18, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Chromosome Aberrations; Translocation, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Philadelphia Chromosome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Dermatologic Agents; Adjuvants, Immunologic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Dexamethasone; Methylprednisolone Acetate; Lenograstim; Cytarabine; Methotrexate; Vincristine; Mercaptopurine
• Other Study ID Numbers: AOM12629_1